Glucagon and insulin are the main regulators of blood glucose. While the actions of insulin are extensively mapped, less is known about glucagon. Besides glucagon's role in glucose homeostasis, there are additional links between the pancreatic alpha cells and the hepatocytes, often collectively referred to as the liver-alpha cell axis, which may be of importance for health and disease. Thus, glucagon receptor antagonism (pharmacological or genetic), which disrupts the liver-alpha cell axis, not only results in lower fasting glucose, but also in reduced amino acid turnover, and dyslipidemia. Here, we review the actions of glucagon on glucose homeostasis, amino acid catabolism, and lipid metabolism in the context of the liver-alpha cell axis. The concept of glucagon resistance is also discussed, and we argue that the various elements of the liver-alpha cell axis may be differentially affected in metabolic diseases such as diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD). This conceptual rethinking of glucagon biology may explain why patients with type 2 diabetes have hyperglucagonemia and how NAFLD disrupts the liver-alpha cell axis, compromising the normal glucagon-mediated enhancement of substrate-induced amino acid turnover and possibly fatty acid beta-oxidation. Glucagon-induced glucose production may, in contrast to amino acid catabolism, however not be affected by NAFLD explaining the diabetogenic effect of NAFLD-associated hyperglucagonemia. Consideration of the liver-alpha cell axis is essential to understand the complex pathophysiology underlying diabetes and other metabolic diseases.

Aims Sacubitril/valsartan is a neprilysin‐inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post‐hoc analysis of a 3‐year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase‐4 inhibitor increases active glucagon‐like peptide‐1 (GLP‐1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase‐4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP‐1. Methods We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured. Results Postprandial plasma glucose increased by 57% (incremental area under the curve 0‐240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6‐2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP‐1 and C‐peptide concentrations increased after sacubitril/valsartan, but insulin and glucose‐dependent insulinotropic polypeptide did not change. Conclusions The glucose‐lowering effects of long‐term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero‐pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study. ClinicalTrials.gov (NCT03893526).

Amino acids stimulate the secretion of glucagon, and glucagon receptor signaling regulates amino acid catabolism via ureagenesis, together constituting the liver-alpha cell axis. Impairment of the liver-alpha cell axis is observed in metabolic diseases such as diabetes. It is, however, unknown whether glucose affects the liver-alpha cell axis. We investigated the role of glucose on the liver-alpha cell axis in vivo and ex vivo. The isolated perfused mouse pancreas was used to evaluate the direct effect of low (3.5 mmol/L) and high (15 mmol/L) glucose levels on amino acid (10 mmol/L arginine)-induced glucagon secretion. High glucose levels alone lowered glucagon secretion, but the amino acid-induced glucagon responses were similar in high and low glucose conditions (p=0.38). The direct effect of glucose on glucagon and amino acid-induced ureagenesis was assessed using isolated perfused mouse livers stimulated with a mixture of amino acids (VaminR, 10 mmol/L) and glucagon (10 nmol/L) during high and low glucose conditions. Urea production increased robustly but was independent of glucose levels (p=0.95). To investigate the whole-body effects of glucose on the liver-alpha cell axis, four groups of mice received intraperitoneal injections of glucose-vamin (2 g/kg, + 3.5 µmol/g, respectively, G/V), saline-vamin (S/V), glucose-saline (G/S), or saline-saline (S/S). Blood glucose did not differ significantly between G/S and G/V groups. Levels of glucagon and amino acids were similar in the G/V and S/V groups (p=0.28). Amino acids may overrule the inhibitory effect of glucose on glucagon secretion and the liver-alpha cell axis may operate independently of glucose in mice.